The long-term goal of this proposal is to elucidate the mechanism of action of decorin in controlling cell proliferation. Our central hypothesis is that the augmented synthesis of decorin around invasive carcinomas represents a mechanism to counteract the invading neoplastic cells. This working hypothesis is based on several key observations: [a] Decorin levels are suppressed in most transformed cells, but markedly increased in quiescent cells. [b] Animals harboring a targeted disruption of decorin develop spontaneous colon tumors and mice with a double knock out of decorin and p53 genes die rapidly of thymic lymphomas, indicating that lack of decorin is permissive for tumorigenesis. [c] Ectopic expression of decorin induces profound cytostatic effects in a wide variety of transformed cells. [d] Decorin interacts with the EGFR and causes a profound attenuation of its tyrosine kinase activity, thereby leading to growth inhibition. [e] We have recently discovered that decorin interacts directly with the Met receptor tyrosine kinase (RTK) causing its rapid intracellular degradation. This body of evidence offers a mechanistic explanation for the heightened decorin levels around invasive carcinomas and indicates that decorin may function as a natural antagonist of neoplastic cells enriched in RTKs, providing yet another layer of complexity to decorin function. Over the next five years we plan to: 1. Decipher the mechanism of action of decorin in downregulating the Met receptor pathway and its role as a pan-RTK inhibitor. 2. Determine the precise structural requirements for decorin/Met interaction, and 3. Investigate the in vivo function of decorin as an anti-oncogenic and anti-angiogenic factor. These concerted research lines should firmly establish the functional roles of decorin in tumorigenesis and shed light on its mechanism of action. The discovery that decorin is a novel antagonist of the Met receptor and that this interaction leads to an overt attenuation of the Met receptor tyrosine kinase and downstream signaling provides the first demonstration of a secreted proteoglycan interacting with this important signal transducing pathway. These findings could lead to the generation of protein mimetics capable of suppressing Met receptor function. The expected results could open novel perspectives for basic cancer research, and could lead to future approaches of cancer prevention and treatment directed at boosting the expression of this proteoglycan, thereby increasing a natural inhibitor of tumor cell growth. PUBLIC HEALTH RELEVANCE: This proposal is focused on expanding our understanding of the mechanism of action of decorin, a small proteoglycan present in the extracellular environment. Decorin's role as a natural inhibitor of tumor growth has been established in recent years. In addition to targeting the epidermal growth factor receptor, decorin targets the Met receptor. Decorin's ability to bind and downregulate multiple receptors involved in tumor progression and metastasis is a key feature that should promote future development into a therapeutic modality against cancer. Thus, we need to define the precise mechanism of action of decorin in inhibiting pathways critical for cancer onset and spreading.